All patient wil receive a combinaison of Pembrolizumab and Debio 1143. Pembrolizumab is a
potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Debio 1143 is an investigational, oral monovalent second mitochondrial-derived activator of
caspases (SMAC) mimetic designed to promote programmed cell death (apoptosis) in tumor cells
and anti-tumour immunity. By antagonizing the activity of inhibitor of apoptosis proteins
(IAPs (X-linked IAP [XIAP], cellular IAP 1 [cIAP1], cellular IAP 2 [cIAP2] and
melanoma-linked IAP [ML-IAP])), Smac mimetics are an interesting treatment approach for
cancer that may foster better tumor responses to chemo/radiotherapy- and/or immuno-therapy.
A Dose escalation part (n= up to 18 patients ) aiming to define the Maximum Tolerated Dose
and the the Recommended Dose for Phase 2 of the proposed combination. A classical 3+3 design
will be used with a fixed dose of Pembrolizumab (200 mg, intravenous , to be administered on
Day 1 of every 3-week cycle i.e. Q3W) and 3 escalating dose level of Debio 1143 administered
daily for 14 days over a 21-day cycle period.
There will be a 24-hour delay between the first and subsequent patients enrolled in each DL
cohort to maximize the safety of enrolled patients.
An extension part (n=28 patients: 14 patients per cohort) aiming to evaluate the clinical
activity of the proposed combination.
Inclusion Criteria:
- Male or female patients aged of at least 18 years on day of signing informed consent.
- Histologically-confirmed diagnosis of Stage III or IV (according to the current
version of the American Joint Committee on Cancer (AJCC)) of PDAC or Stage IV CRC.
Note: pancreatic endocrine tumors are not eligible.
- Previous treatment in the metastatic / advanced stage: PDAC: at least one line of
chemotherapy and CRC: at least one line of chemotherapy containing 5-FU, oxaliplatin,
irinotecan, plus bevacizumab if patient is eligible, plus anti-EGFR if CRC with RAS
wild-type.
- Documented radiological disease progression as per RECIST V1.1 at time of inclusion.
- At least one measurable lesion according to RECIST v1.1.
- Presence of at least one tumor lesion with a diameter ≥20 mm, visible by medical
imaging and accessible to repeatable percutaneous (needle biopsies 18 gauge or larger)
sampling that permit core needle biopsy (ideally 4 cores) without unacceptable risk of
a major procedural complication.
Note: 1. endoscopic biopsies are not allowed. 2. Lymph nodes, lung and RECIST target
lesions are not suitable for de novo biopsies.
- Availability of a representative formalin-fixed and paraffin-embedded (FFPE) primary
and/or metastatic tumor tissue with an associated pathology report.
Note: Fine needle aspirates, and bone biopsies do not satisfy the requirement for tumor
tissue.
Note : If adequate tissue from distinct timepoints (such as time of initial diagnosis and
time of disease recurrence and/or multiple metastatic tumors is available), priority should
be given to the tissue most recently collected (ideally subsequent to the most recent
systemic therapy).
- ECOG Performance Status (PS) 0 or 1 (See Appendix 1).
- Life expectancy of at least 12 weeks.
- Demonstrate adequate organ function as defined in table below, all screening
laboratory tests should be performed within 7 days prior C1D1.
HEMATOLOGICAL Absolute neutrophil count (ANC) ≥ 1.5 G/L Platelets ≥ 100 G/L Hemoglobin ≥ 9
g/dL (without transfusion within 7 days) RENAL Serum creatinine OR Creatinine clearance
according to CKD-EPI ≤ 1.5 × Upper Limit of Normal (ULN) OR ≥ 50 mL/min/1.73m2 HEPATIC
Serum total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert disease for whom a
total serum bilirubin ≤ 3 x ULN is acceptable). OR Direct bilirubin ≤ ULN for patients with
total bilirubin levels > 1.5 × ULN ASAT and ALAT ≤ 3 × ULN (or ≤ 5 × ULN in case of liver
metastasis or hepatic infiltration) COAGULATION INR and Activated Partial Thromboplastin
Time (aPTT) ≤ 1.5 × ULN Note: This is applicable only for patients not receiving an
anticoagulant treatment: patients receiving therapeutic anticoagulation must be on stable
dose.
- Able to swallow and retain orally administered medication.
- Minimal wash-out period for the following treatments (= minimal delay between the last
dose of these treatments and C1D1): Chemotherapy, tyrosine kinase inhibitor or
radiation therapy : 2 weeks; Immunosuppressive medication: 4 weeks, with the
exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at
physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent
corticosteroid; Any investigational agents: 5 half-lives of the investigation agent
with a minimum of 2 weeks; Monoclonal antibodies: 4 weeks; Major surgical procedure,
open biopsy (excluding skin cancer resection or screening biopsy), or significant
traumatic injury : 2 weeks; Live vaccines : 4 weeks.
- Women of child-bearing potential must have a negative serum pregnancy test at
Screening and must agree to use 2 effective forms of contraception from the time of
the negative pregnancy test up to 120 days after the last dose of study drugs.
- Fertile men must agree to use contraceptive measures up to 120 days after the last
dose of study drugs.
- Patients who understand, sign, and date the written voluntary informed consent form at
the screening visit prior to any protocol-specific procedures. Patient should be able
and willing to comply with study visits and procedures as per protocol.
- Patients must be covered by a medical insurance.
Exclusion Criteria:
- Patients amenable to therapy with curative intent.
- Patient participating to another clinical trial with a medicinal product.
- Patients with microsatellite instability (MSI)-high or mismatch repair MMR-deficient
tumors.
- Patients who have not recovered from adverse events (i.e. > Grade 1 according to NCI
CTCAE v5.0 See Appendix 5) due to prior treatment with anti-cancer agents with
exception of Grade 2 neuropathy, any Grade alopecia or lab values presented in
criteria I10.
- Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTL-A4
and any ICIs or IAP inhibitors.
- Patients who have a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone potentially
curative therapy.
- Patients with known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Patients with previously treated brain metastases may
participate provided they are stable (without evidence of progression by imaging for
at least four weeks prior to C1D1 and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids (at doses higher than 10 mg/d of methylprednisolone or equivalent) for at
least 4 weeks prior C1D1.
- Patients with a history of autoimmune disease requiring systemic treatment within the
past 3 months or a documented history of clinically severe autoimmune disease, or a
syndrome that requires systemic steroids (at doses higher than 10 mg/d of
methylprednisolone or equivalent) or immunosuppressive agents.
- Patients with history of (non-infectious) pneumonitis that required steroids, evidence
of interstitial lung disease or active, non-infectious pneumonitis.
- Patients with an evidence of active infection requiring systemic therapy.
- Patients with a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial.
- Patients with a history of uncontrolled or symptomatic, clinically significant
cardiovascular disease : stroke, myocardial infarction, angina pectoris, arrhythmias,
congestive heart failure (NYHA Class >2), or myocarditis within 6 months prior to
first study drug administration.
- Patient with a history of organ transplant including stem cell allograft.
- Patients receiving or to be treated during the treatment period with one of the
following forbidden treatment: Any anti-cancer systemic chemotherapy, targeted therapy
or biological therapy including any immunotherapy not mentioned in this protocol; Any
investigational agents other than Debio-1143; Radiation therapy; Live vaccines, Major
surgery; Corticosteroids for any purpose other than to modulate symptoms from an event
of clinical interest of suspected immunologic etiology. The use of physiologic doses
of corticosteroids may be approved after consultation with the sponsor; Strong P-gp
inhibitors or inducers.
- Patients with hypersensitivity to Pembrolizumab or any of its excipients.
- Patients with a known history of active TB (Bacillus Tuberculosis).
- Patients with : Active hepatitis B (chronic or acute; defined as having a positive
hepatitis B surface antigen [HBsAg] test at screening), or Active hepatitis C.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is
negative for HCV RNA, or HIV infection.
- Patients with known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Patients who are pregnant or breastfeeding, or expecting to conceive or father
children within the projected duration of the trial, starting with the screening visit
through 120 days after the last dose of trial treatment.
